Chemical compounds

Abstract

Histamine H 2 -antagonists of the formula ##STR1## wherein p is 1 or 2; R 1 is hydroxy, amino, substituted amino or a 5- to 9-membered fully saturated nitrogen-containing heterocyclic ring attached via its nitrogen atom; m is an integer of from 0 to 2; n is an integer of from 2 to 4; Z is sulfur, oxygen or methylene; and A is an optionally substituted phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl ring; and nontoxic pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof are novel anti-ulcer agents. Intermediates and processes for their preparation are disclosed.

We claim: 
     
       1. A compound of the formula ##STR60## wherein p is 1 or 2; R 1  is hydroxy or NR 2  R 3  ;   R 2  and R 3  each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, (lower)alkylthio(lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R 2  is hydrogen, R 3  may also be cyclo(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, piperazino(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)alkoxy, 2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidino, A'--(CH 2 ) m'  Z'(CH 2 ) n'  --, phenyl, phenyl(lower)alkyl, substituted phenyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino; or R 2  and R 3 , taken together, may be --CH 2  CH 2  X(CH 2 ) r  --;   r is an integer of from 1 to 3, inclusive;   X is methylene, sulfur, oxygen or N-R 4 , provided that, when r is 1, X is methylene;   R 4  is hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkanoyl or benzoyl;   m and m' each are independently an integer of from zero to 2, inclusive;   n and n' each are independently an integer of from 2 to 4, inclusive;   Z and Z' each are independently sulfur, oxygen or methylene;   A and A' each are independently phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, ##STR61##  and --(CH 2 ) q  NR 5  R 6 , and the second substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy;   q is an integer of from 0 to 6, inclusive; R 14  and R 15  independently are hydrogen or (lower)alkyl, or, if R 14  is hydrogen, R 15  also may be (lower)alkanoyl or benzoyl, or R 14  and R 15 , taken together, may be ethylene; and   R 5  and R 6  each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkoxy(lower)alkyl, cyclo(lower)alkyl or phenyl, provided that R 5  and R 6  may not both be cyclo(lower)alkyl or phenyl; or R 5  and R 6 , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino;   or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.   
     
     
       2. A compound of claim 1 having the formula ##STR62## wherein p is 1 or 2; R 2  and R 3  each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, (lower)alkylthio(lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R 2  is hydrogen, R 3  may also be cyclo(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, piperazino(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)alkoxy, 2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidino, A'--(CH 2 ) m'  Z'(CH 2 ) n'  --, phenyl, phenyl(lower)alkyl, substituted phenyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino; or R 2  and R 3 , taken together, may be --CH 2  CH 2  X(CH 2 ) r  --;   r is an integer of from 1 to 3, inclusive;   X is methylene, sulfur, oxygen or N-R 4 , provided that, when r is 1, X is methylene;   R 4  is hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkanoyl or benzoyl;   m and m' each are independently an integer of from zero to 2, inclusive;   n and n' each are independently an integer of from 2 to 4, inclusive;   Z and Z' each are independently sulfur, oxygen or methylene;   A and A' each are independently phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, ##STR63##  and --(CH 2 ) q  NR 5  R 6 , and the second substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy;   q is an integer of from 0 to 6, inclusive; R 14  and R 15  independently are hydrogen or (lower)alkyl, or, if R 14  is hydrogen, R 15  also may be (lower)alkanoyl or benzoyl, or R 14  and R 15 , taken together, may be ethylene; and   R 5  and R 6  each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkoxy(lower)alkyl, cyclo(lower)alkyl or phenyl provided that R 5  and R 6  may not both be cyclo(lower)alkyl or phenyl; or R 5  and R 6 , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino;   or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.   
     
     
       3. A compound of claim 1 having the formula ##STR64## wherein p is 1 or 2; R 2  and R 3  each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, 2-fluoroethyl or 2,2,2-trifluoroethyl, or, when R 2  is hydrogen, R 3  also may be pyrrolidino(lower)alkyl, piperidino(lower)alkyl, piperazino(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, hydroxy, A'--(CH 2 ) m'  Z'(CH 2 ) n'  --, phenyl(lower)alkyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino;   m and m' each are independently an integer of from zero to 2, inclusive;   n and n' each are independently an integer of from 2 to 4, inclusive;   Z and Z' each are independently sulfur, oxygen or methylene;   A and A' each are independently phenyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, ##STR65##  and --(CH 2 ) q  NR 5  R 6 , and the second substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy;   q is an integer of from 0 to 6, inclusive; R 14  and R 15  independently are hydrogen or (lower)alkyl, or R 14  and R 15 , taken together, may be ethylene; and   R 5  and R 6  each are independently hydrogen, (lower)alkyl, (lower)alkenyl or (lower)alkynyl; or R 5  and R 6 , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino;   or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.   
     
     
       4. A compound of claim 1 having the formula ##STR66## wherein p is 1 or 2; R 2  and R 3  each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl or cyclo(lower)alkyl(lower)alkyl, or, when R 2  is hydrogen, R 3  also may be substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, A'--(CH 2 ) m'  Z'(CH 2 ) n'  --, phenyl(lower)alkyl or 3,4-methylenedioxybenzyl;   m and m' each are independently zero or 1;   n and n' each are independently 2 or 3;   Z and Z' each are independently sulfur, oxygen or methylene;   A and A' each are independently phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl; provided that A and A' independently may contain one or two substituents, the first substituent being selected from (lower)alkyl, ##STR67##  and --CH 2  NR 5  R 6 , and the second substituent being selected from (lower)alkyl;   R 14  and R 15  independently are hydrogen or (lower)alkyl, or R 14  and R 15 , taken together, may be ethylene; and   R 5  and R 6  each are independently hydrogen or (lower)alkyl; or R 5  and R 6 , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino;   or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.   
     
     
       5. A compound of claim 1 having the formula ##STR68## wherein p is 1 or 2; Z is sulfur or methylene; R 2  and R 3  each are independently hydrogen or (lower)alkyl, or, when R 2  is hydrogen, R 3  also may be (lower)alkenyl, (lower)alkynyl, phenyl(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, or ##STR69## R 16  is methyl and R 13  is hydrogen or methyl, or R 16  and R 13 , taken together with the nitrogen atom to which they are attached, may be piperidino; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       6. A compound of claim 1 having the formula ##STR70## wherein p is 1 or 2; Z is sulfur or methylene; R 14  and R 15  independently are hydrogen or methyl, or, R 14  and R 15 , taken together, may be ethylene; and R 2  and R 3  each are independently hydrogen or (lower)alkyl, or, when R 2  is hydrogen, R 3  may also be (lower)alkenyl, (lower)alkynyl, ##STR71## or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       7. A compound of claim 1 having the formula ##STR72## wherein p is 1 or 2; Z is sulfur or methylene; R 2  and R 3  each are independently hydrogen or (lower)alkyl, or when R 2  is hydrogen, R 3  also may be (lower)alkenyl, (lower)alkynyl or ##STR73## and R 13  is hydrogen or methyl; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       8. A compound of claim 1 having the formula ##STR74## wherein p is 1 or 2; Z is sulfur or methylene; R 2  and R 3  each are independently hydrogen or (lower)alkyl, or, when R 2  is hydrogen, R 3  also may be (lower)alkenyl, (lower)alkynyl, phenyl(lower)alkyl, 3,4-methylenedioxybenzyl or ##STR75## and R 13  is hydrogen or methyl; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       9. A compound of claim 1 having the formula ##STR76## wherein p is 1 or 2; and R 2  and R 3  each are independently hydrogen or (lower)alkyl, or, when R 2  is hydrogen, R 3  also may be (lower)alkenyl, (lower)alkynyl or ##STR77## or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       10. A compound of claim 1 having the formula ##STR78## wherein p is 1 or 2; Z is sulfur or methylene; R 2  and R 3  each are independently hydrogen or (lower)alkyl, or, when R 2  is hydrogen, R 3  also may be (lower)alkenyl, (lower)alkynyl or ##STR79## and R 5  and R 6  each are independently hydrogen or (lower)alkyl, or, R 5  and R 6 , taken together with the nitrogen atom to which they are attached, may be piperidino; or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       11. A compound of claim 1 having the formula ##STR80## wherein p is 1 or 2; Z is oxygen or sulfur; R 2  and R 3  each are independently hydrogen or (lower)alkyl, or, when R 2  is hydrogen, R 3  also may be (lower)alkenyl, (lower)alkynyl or ##STR81## and R 5  and R 6  each are independently hydrogen or (lower)alkyl, or, when R 5  is hydrogen, R 6  also may be (lower)alkenyl or (lower)alkynyl; or R 5  and R 6 , taken together with the nitrogen to which they are attached, may be pyrrolidino, methylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, homopiperidino or heptamethyleneimino; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       12. A compound of claim 1 having the formula ##STR82## wherein p is 1 or 2; Z is oxygen or sulfur; R 2  and R 3  each are independently hydrogen or (lower)alkyl, or, when R 2  is hydrogen, R 3  may be (lower)alkenyl, (lower)alkynyl, or ##STR83## or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       13. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       14. The compound of claim 1 which is 3-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       15. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       16. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(n-propyl)amino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       17. The compound of claim 1 which is 3-allylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       18. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl(methylthio]ethylamino}-4-(2-propynyl)amino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       19. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       20. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       21. The compound of claim 1 which is 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       22. The compound of claim 1 which is 3-{4-(5-dimethylaminomethyl-2-furyl)butylamino}-4-methylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       23. The compound of claim 1 which is 3-methylamino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       24. The compound of claim 1 which is 3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       25. The compound of claim 1 which is 3-{2-[(2-guanidinothiazol-3-yl)methylthio]ethylamino}-4-(2-propynyl)amino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       26. The compound of claim 1 which is 3-amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       27. The compound of claim 1 which is 3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       28. The compound of claim 1 which is 3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       29. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       30. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       31. The compound of claim 1 which is 3-amino-4-{3-[3-(4-methylpiperidinomethyl)phenoxy]propylamino}-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       32. 3-Amino-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       33. 3-Amino-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-2-1,2,5-thiadiazole 1-oxide monohydrate. 
     
     
       34. 3-Amino-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide hydrochloride. 
     
     
       35. The compound of claim 1 which is 3-benzylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       36. The compound of claim 1 which is 3-{2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       37. The compound of claim 1 which is 3-amino-4-{2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       38. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       39. The compound of claim 1 which is 3-amino-4-{4-(5-dimethylaminomethyl-2-furyl)butylamino}-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       40. The compound of claim 1 which is 3-amino-4-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       41. The compound of claim 1 which is 3-butylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       42. The compound of claim 1 which is 3-cyclopropylmethylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       43. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-[(2-pyridyl)methylamino]-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       44. The compound of claim 1 which is 3-amino-4-{3-[3-(4-methylpiperidinomethyl)phenoxy]propylamino}-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       45. The compound of claim 1 which is 4-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-3-(1-propylamino)-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       46. The compound of claim 1 which is 3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       47. The compound of claim 1 which is 3-{3-[3-(hexamethyleneiminomethyl)phenoxy]propylamino}-4-methylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       48. The compound of claim 1 which is 3-[3-(3-dimetylaminomethylphenoxy)propylamino]-4-methylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       49. The compound of claim 1 which is 3-amino-4-{3-[3-(hexamethyleneiminomethyl)phenoxy]propylamino}-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       50. The compound of claim 1 which is 3-amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       51. The compound of claim 1 which is 3-amino-4-{3-[3-(heptamethyleneiminomethyl)phenoxy]propylamino}-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       52. The compound of claim 1 which is 3-amino-4-{2-[(2-{2-methylguanidino}thiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       53. The compound of claim 1 which is 3-methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       54. The compound of claim 1 which is 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       55. The compound of claim 1 which is 3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       56. The compound of claim 1 which is 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1,1-dioxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       57. The compound of claim 1 which is 3-amino-4-[3-(3-guanidinophenoxy)propylamino]-1,2,5-thiadiazole 1-oxide or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof. 
     
     
       58. A compound of claim 1 having the formula ##STR84## wherein p is 1 or 2; Z is sulfur or methylene; R 2  and R 3  each are independently hydrogen or (lower)alkyl, or, when R 2  is hydrogen, R 3  also may be (lower)alkenyl, (lower)alkynyl, phenyl(lower)alkyl, 3,4-methylenedioxybenzyl or ##STR85## R 16  is methyl and R 13  is hydrogen or methyl, or R 16  and R 13 , taken together with the nitrogen atom to which they are attached, may be pyrrolidino, morpholino, piperidino, methylpiperidino, homopiperidino or heptamethyleneimino; or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.